Probe powerfully records neural circuits during behavior

Trying to document how single brain cells participate in networks that govern behavior is a daunting task. Brain probes called Neuropixels, which feature high-density silicon arrays, have enabled scientists to collect electrophysiological data of this nature from a variety of animals. These include fish, reptiles, rodents and primates, as well as humans.

Neuropixels, which come in several versions, record electrical activity from hundreds to thousands of neurons simultaneously. Neurons are nerve cells that receive, process and transmit information. 

While the data collected has led to insights on the neural basis of perception and decision-making, those probes cannot sample fine-scale brain structures. They also are limited in resolving (separately distinguishing) the electrical fields around individual brain cells. 

A newly developed probe, called Neuropixels Ultra, overcomes some key technical challenges in recording the cell type and activity of thousands of individual cells across many brain regions during a single experiment.  

The probe is essentially an implantable, voltage-sensing camera that can capture flat images of a brain cell’s electrical field. 

“We developed a silicon probe with much smaller and denser recording sites than previous designs,” said Nick Steinmetz, the corresponding author of a report on tests of the probe’s function. Steinmetz is an associate professor of neurobiology and biophysics at the University of Washington School of Medicine in Seattle.  

The Steimnetz lab is part of the International Brain Laboratory and the Neuropixels Consortium.

The recent project brought together scientists from several neuroscience and bioengineering labs across the United States, as well as in Japan, Germany, Belgium, China, Norway, England and Italy. 

Their paper appears Sept. 30 in a Cell Press scientific journal, Neuron. 

The project is part of the National Institutes of Health’s “Brain Research Through Advancing Innovative Neurotechnologies,” also known as the BRAIN Initiative.  The initiative was established to develop and apply innovative technologies to map brain circuits and understand their functions, as well as other brain research tools.  The overarching goal is to produce a dynamic picture of the brain that shows how individual cells and complex neural circuits interact in time and space. 

The new ultra-high density Neuropixels Ultra probe is a significant step in that direction.  

By obtaining more detailed information about the electrical field surrounding a brain cell than was previously possible, the new probe improved scientists’ ability to detect and classify individual cells. 

For example, the researchers conducted recordings of the mouse visual cortex — an area near the back of the brain that processes and interprets information coming from the eyes. The scientists were able to detect twice as many brain cells, compared with recordings with other Neuropixels versions. They also could distinguish three cortical cell subtypes from each other and from other neurons. Being able to detect specific cell subtypes is important in studying brain circuits.  

Because the probe gathered data from smaller sites, it predictably had higher noise levels per channel than do earlier probes. But because it sampled 10 times more recording sites, it still offered better data quality.  

Neuropixels Ultra was more precise in estimating the spatial position of spikes, the rapid rise and sudden fall of an electrical impulse from a brain cell. It was better at separating spikes from one neuron and not attributing them to nearby neurons. This spatial precision helped increase the yield of sortable, visually responsive neurons. Such measurements could help scientists more accurately decode and track brain cell performance related to visual stimuli.  

The researchers also used Neuropixels Ultra to determine how prevalent small-footprint extracellular spikes were across different brain regions and in species other than mice. Thes animals included electric fish, bearded dragon lizards and pigtailed macaques.  

“These small spatial footprints, which are difficult to detect with lower density probes, are consistently detected with Neuropixels Ultra,” the scientists observed. They also found that the spatial footprints of cell types that were genetically identified were different for each cell type. This information could help, for example, in determining which cells are present and their distinctive electrical activity.  

The researchers concluded that there were tradeoffs between the newer and older probes, depending on the type of experiments a lab conducts. Although the newer probe has a smaller site size and spacing, it also has what its developers describe as “unprecedented” resolution. By contrast, the older probes have a larger vertical recording span. Nonetheless, the recent findings “highlight the advantages of electrophysiological probes with increased site density for a wide range of neurosciences applications,” the researchers noted.  

The first authors of the paper are Zhiwen Ye, a postdoctoral neuroscientist in the Steinmetz lab at the UW School of Medicine, and Andrew M. Shelton, of the MindScope Program and Institute for Neural Dynamics as well as the Behavioral Group at the Allen Institute for Brain Science.

This research program was funded by the NIH BRAIN Initiative (U01NS113252). Additional support was provided by  Pew Biomedical Scholars Program,  Klingenstein-Simons Fellowship in Neuroscience,  Max Planck Society,  European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (834446 and AdG 695709),  National Institutes of Health (R01NS118448 and R01 NS075023), the Wellcome Trust (PRF 201225, 224688, SHWF 221674, and 204915),  Giovanni Armenise Harvard Foundation, The Human Technopole,  National Science Foundation (IOS 211500) and a Boehringer Ingelheim Fonds Ph.D. Fellowship. Computational modeling work was supported by the European Union Horizon 2020 Research and Innovation Programme (945539), Human Brain Project (SGA3 and 101147319), and EBRAINS 2.0. 

The BRAIN Initiative is a registered trademark of the U.S. Department of Health and Human Services.  

Editor’s note: The content of the Neuron research paper and of this news release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

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